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  • UKCTOCS was approved by the UK North-West Multicentre Research Ethics Committee (International Standard Randomised Controlled Trial, number ISRCTN22488978; ClinicalTrials.gov NCT00058032). Approval for the current analysis was obtained from the Joint UCL/UCLH Ethics Committee on the Ethics of Human Research (Committee A), Ref: 07/H0714/81, ethical approval granted on 11th April 2013). The main trial design, including details of recruitment and screening techniques has been detailed elsewhere. [23,24] In brief therefore, over 1.2 million women aged 50–74 in the UK were invited to be screened for ovarian cancer. Over 200,000 women were recruited between April 2001 and October 2005 through 13 centres in England, Wales and Northern Ireland. Women completed a recruitment questionnaire and provided written consent to use of their data in secondary studies. They were randomised to control (no intervention) or annual screening using either serum CA125 or transvaginal ultrasound (TVS) based strategy. All participants were followed up using their National Health Service (NHS) number through the appropriate national agencies for cancer registrations/deaths as well as by postal questionnaires. The most recent cancer registrations for this analysis were received from Health and Social Care Information Centre (HSCIC) on 17th June 2014. Women were also linked to their Hospital Episode Statistics (HES) records that were available for the period 1st April 2001 to 31st March 2010 for participants treated in the English NHS. HES is an electronic administrative database funded by the NHS which holds records on both inpatient and outpatient procedures for patients resident in England. [25] The study population consisted of all women resident in England, enrolled in UKCTOCS, who were diagnosed with EC between April 2001 and December 2009, and for whom HES records were available. Patients with a concurrent diagnosis (synchronous) of primary peritoneal or ovarian cancer in addition to primary endometrial cancer, missing stage or incomplete HES data (possibly due to patients transferring their care outside the English NHS) were excluded. The notification of EC diagnosis was received from multiple sources, the cancer registries (through the Health and Social Care Information Centre (HSCIC) and HES (Hospital Episode Statistics) which were searched using the ICD-10 codes of C54 (malignant neoplasm of corpus uterus) and C55 (malignant neoplasm of uterus, part unspecified), from self-reporting on the postal follow-up questionnaire or direct contact from the volunteer or their physician. Hospital records which included surgical and pathological reports were retrieved and independently reviewed by a clinician using an Outcomes Review form who confirmed EC diagnosis, stage using the FIGO classification,[26] grade and histological subtype. UKCTOCS trial data provided patient characteristics including date of birth, Body Mass Index (BMI) collected at recruitment, hospital records of women diagnosed with EC and date of death. For confidentiality reasons only the month and year was available for the date of birth and date of death; each entry was arbitrarily assigned to the 15th of the relevant month. HES provided date of admission, date of transfer or discharge, diagnosis (as ICD-10 codes),[27] procedures undertaken (coded using the Office of Population Censuses and Surveys (OPCS) Classification of Surgical Operations version 4 codes),[28] treatment specialty, Healthcare Resource Group (HRG)[29] codes for reimbursement, and patient deprivation (measured as the Index of Multiple Deprivation (IMD) which is a geographically determined index based on areas of approximately 1500 people). [30] We included all HES inpatient and outpatient episodes related to EC. Assignment for inpatient procedures was based primarily on OPCS-4 procedure codes taking into account the HRG code and treatment speciality. Outpatient records were less complete and procedure codes were rarely available. Outpatient records lacking procedure codes were only included where the fields coding the main specialty or the treatment speciality contained a code relating to either oncology or gynaecology. Investigations occurring within six months prior to diagnosis were included. Procedures were further classified into surgery (hysterectomy, BSO and pre-surgical investigations), adjuvant therapy, and further treatment (including management of complications). Estimating costs of inpatient and outpatient episodes: Costs were assigned to episodes of care on the basis of the associated HRG code. [29] This is a type of Diagnosis Related Groups (DRG) used to assign a reimbursement tariff in the English NHS. Version (3.5) was used, which allowed assignment of the 2005 Payment by Results (PbR) tariff to episodes from the entire period 2001 to 2010. [31] We then inflated the cost to 2012/13 prices using the Hospital & Community Health Services Index. [32] Finally we multiplied each cost by 1.08 which is the average Market Forces Factor for Hospitals in the English NHS. [33] Market Forces Factors are applied to payments generated from HRG codes to adjust payments for unavoidable differences in costs relating to the geographic location of each hospital. [34] In addition to estimating cost on the basis of HRG code we adjusted costs for extended length of stay. A maximum length of stay is specified for each HRG code and length of stay beyond this point is reimbursed at a daily tariff specific to that HRG. Where patient length of stay during a spell in hospital exceeded the maximum specified for the HRG code we applied the appropriate excess bed day adjustment to the estimated cost. PbR tariffs distinguish inpatient and outpatient procedures, and (for inpatient procedures) elective versus emergency admissions. We assumed that all inpatient admissions were elective procedures as we lacked data on the type of inpatient admission. Hospital admissions are remunerated per spell (from admission to discharge). Generally a spell consists of one episode of care, but occasionally it may consist of more than one episode. In the latter situation hospitals are remunerated according to the dominant procedure for the component episodes (typically the most expensive). We applied the costs for the most expensive episode for spells of care consisting of multiple episodes. Inpatient episodes with missing HRG code (20%) were assigned a code on the basis of OPCS procedure codes. The majority of outpatient episodes had no HRG or OPCS code assigned. We identified records of chemotherapy and radiotherapy on the basis of the interval between admissions and the assigned treatment specialty (medical or clinical oncology). These records were assigned the appropriate outpatient PbR tariff for radiology or chemotherapy. The remaining outpatient episodes were assigned the average outpatient cost for 2012/13 of £135 per episode. [32] We had missing cost data in the form of censored observations where five year follow-up date and date of death exceeded 31st March 2010 (data available from HES). We had further missing data on histological subtype (0.4%), grade (3.2%), IMD (0.4%), and BMI (0.8%). IMD scores were used to partition patients into quintiles. We applied a binary classification of histological subtype which grouped Atypical Endometrial Hyperplasia (AEH) and Endometrioid EC versus all other EC histological subtypes. We used multiple Imputation (MI) to impute the missing data. [35] MI is a principled approach which fully captures the additional uncertainty generated in the imputation process. [36–37] Further details on the application of MI are provided in the supporting information (S1 File). Costs arising in years following the first year after diagnosis were discounted at 3.5% according to recommendations on technology assessment by the National Institute of Health and Care Excellence (NICE). [38] FIGO stage was specified as follows: stages IA & IB; stage IC; stage II; stage III; stage IV. We subdivided costs into three categories: surgery; adjuvant therapy and further treatment as detailed above. Costs accumulated at two years after diagnosis are reported for the subset of patients with a minimum of two years follow-up in HES (diagnosis prior to 31st March 2008). Total costs (after imputation of missing data) were determined for all patients at five years from diagnosis, with non-parametric 95% confidence intervals estimated from 1,000 bootstrap replicates of the data (details in appendix). Costs accumulated at five years after diagnosis for patients with complete cost data (diagnosis prior to 31st March 2005) are provided in the supplementary material (Table A in S1 File). Regression modelling was undertaken to explore the impact of patient characteristics on cost. We fitted Ordinary Least Squares (OLS) regression models to each of the three cost categories and to total costs. We pre-specified the following covariates: age, year of diagnosis, histological subtype (as Endometrioid Carcinoma/AEH or other), grade, stage, IMD quintile, Charlson score[39] and BMI. We categorised BMI as under 18.5; 18.5 to 30; over 30. Year of diagnosis was specified as the number of years following the earliest diagnosis date in the sample (January 2002). Charlson scores were determined from ICD-10 codes recorded for the hysterectomy (or the first inpatient procedure following diagnosis in the absence of hysterectomy) after exclusion of codes for cancer or metastases. Dates of death were available until June 2014. Deaths were assigned to EC where the original underlying cause of death was EC (ICD-10 codes C54.0, C54.1). Regression modelling was used to investigate the impact of patient characteristics on survival over the total observation time considering both all cause and cancer specific mortality. Cox proportional hazards models were fitted to the data that adjusted for the same covariates selected for the cost analysis (detailed above). A Therneau and Grambsch test was applied to assess the appropriateness of an assumption of proportional hazards. [40] All statistical analysis was undertaken in Stata, version 13.1. [41]
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